JP6027893B2 - 性ホルモン結合グロブリン(shbg)に対する天然アンチセンス転写物の阻害による性ホルモン結合グロブリン(shbg)関連疾患の治療 - Google Patents
性ホルモン結合グロブリン(shbg)に対する天然アンチセンス転写物の阻害による性ホルモン結合グロブリン(shbg)関連疾患の治療 Download PDFInfo
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Description
配列番号1:性ホルモン結合グロブリン(SHBG)、転写物変異型、mRNA(NCBI登録番号:NM_001040);配列番号2:天然SHBGアンチセンス配列(FXR2−登録番号:NM_004860.3);配列番号3:天然SHBGアンチセンス配列SAT2;針意列番号4乃至17:アンチセンスオリゴヌクレオチド。*はホスホチオエート結合を示す。
本発明のいくつかの態様について、例示のための応用例を参照して以下に説明する。種々の特定の細部、関係、および方法は、本発明の完全な理解のために記載されていることを理解されたい。しかし、本発明を、1以上の特定の細部を用いることなく、または他の方法を用いて実施できることは、当業者には容易に理解されよう。本発明は、行為や事象の順序によって限定されず、いくつかの行為は、異なる順序で、および/または他の作用または事象と同時に発生し得る。さらに、すべての例示された行為または事象は、本発明による方法を実施するために必ずしも必要ではない。
本明細書で使用される用語の選択は、特定の実施形態を説明する目的でされたものであり、本発明を限定することを意図するものではない。本明細書で使用される場合、単数形の「a」、「an」、及び「the」は文脈において明らかに別記されない限り、複数形の内容も含むものとする。さらに、用語「含む」、「含める」、「有する」、「もつ」またはその変化形は、本明細書および/または添付の請求項において使用される場合、用語「包含する」と同様に非排他的な意味で用いられるものとする。
標的::一実施形態において、該標的は、限定することなくSHBGに関連するセンスおよび/またはアンチセンスの非コードおよび/またはコード配列を含めた、性ホルモン結合グロブリン(SHBG)の核酸配列を含む。
外来性核酸の宿主細胞または生体内への輸送は、細胞中または生体中の核酸を直接検出するステップによって評価され得る。そのような検出は、当技術分野において周知のいくつかの方法によって達成し得る。例えば、外来性核酸の存在は、サザンブロットまたは核酸に関連するヌクレオチド配列を特異的に増幅するプライマーを使用するポリメラーゼ連鎖反応(PCR)技術によって検出し得る。外来性核酸の発現も遺伝子発現分析を含む従来の方法を使用して測定し得る。例えば外来性核酸から生成されるmRNAはノーザンブロットおよび逆転写PCR(RT−PCR)を使用して検出および定量し得る。
本発明の化合物は、診断、治療および予防のためにならびに研究用試薬およびキットの構成要素として利用され得る。さらに、優れた特異性をもって遺伝子発現を阻害できるアンチセンスオリゴヌクレオチドは、当業者によって特定の遺伝子の機能を解明するため、または生物学的経路の種々のメンバー間の機能を区別するために使用されることが多い。
本発明のオリゴヌクレオチドの他の修飾は、オリゴヌクレオチドの活性、細胞分布または細胞への取り込みを増強する1以上の成分またはコンジュゲートへのオリゴヌクレオチドの化学的連結を含む。これらの成分またはコンジュゲートは、1級または2級ヒドロキシル基などの官能基に共有結合したコンジュゲート基を含み得る。本発明のコンジュゲート基は、干渉物質、レポーター分子、ポリアミン、ポリアミド、ポリエチレングリコール、ポリエーテル、オリゴマーの薬力学特性を増強する基、およびオリゴマーの薬物動態特性を増強する基を含む。典型的なコンジュゲート基は、コレステロール、脂質、リン脂質、ビオチン、フェナジン、葉酸、フェナントリジン、アントラキノン、アクリジン、フルオレセイン、ローダミン、クマリン、および色素を含む。本発明の文脈において薬力学特性を増強する基は、取り込みを改善し、分解への耐性を増強し、および/または標的核酸との配列特異的ハイブリダイゼーションを強化する基を含む。本発明の文脈において薬物動態特性を増強する基は、本発明の化合物の取り込み、分散、代謝または排出を改善する基を含む。代表的コンジュゲート基は、1992年10月23日出願の国際特許出願PCT/US92/09196および米国特許第6,287,860号、「Antisense inhibition of MEKK2 expression」において開示されており、これらはともに参照により本明細書に組み込まれる。コンジュゲート成分は、以下に限定されないが、コレステロール成分、コール酸、チオエーテル(例えばヘキシル−S−トリチルチオール)、チオコレステロール、脂肪族鎖(例えばドデカンジオールまたはウンデシル残基)、リン脂質(例えばジ−ヘキサデシル−rac−グリセロールまたはトリエチルアンモニウム1,2−ジ−O−ヘキサデシル−rac−グリセロ−3−H−ホスホネート)、ポリアミンまたはポリエチレングリコール鎖、あるいはアダマンタン酢酸、パルミチル成分、またはオクタデシルアミンもしくはヘキシルアミノ−カルボニル−オキシコレステロール成分などを含む。本発明のオリゴヌクレオチドは、活性原薬、例えばアスピリン、ワルファリン、フェニルブタゾン、イブプロフェン、スプロフェン、フェンブフェン、ケトプロフェン、(S)−(+)−プラノプロフェン、カプロフェン、ダンシルサルコシン、2,3,5−トリヨード安息香酸、フルフェナム酸、フォリン酸、ベンゾチアジアジド、クロロチアジド、ジアセピン、インドメチシン、バルビツール酸、セファロスポリン、サルファ剤、抗糖尿病薬、抗菌剤または抗生物質ともコンジュゲート形成され得る。
本発明の化合物は、取り込み、分散および/または吸収の補助ために、例えばリポソーム、受容体−標的分子、経口、直腸、局所または他の製剤として、他の分子、分子構造または化合物と、混合物と混合、封入、コンジュゲート化または他の方法で結合され得る。そのような取り込み、分散および/または吸収を補助する製剤の調製について記載した代表的米国特許としては、以下に限定されないが、米国特許第5,108,921号;第5,354,844号;第5,416,016号;第5,459,127号;第5,521,291号;第5,543,165号;第5,547,932号;第5,583,020号;第5,591,721号;第4,426,330号;第4,534,899号;第5,013,556号;第5,108,921号;第5,213,804号;第5,227,170号;第5,264,221号;第5,356,633号;第5,395,619号;第5,416,016号;第5,417,978号;第5,462,854号;第5,469,854号;第5,512,295号;第5,527,528号;第5,534,259号;第5,543,152号;第5,556,948号;第5,580,575号;および第5,595,756号が挙げられ、それぞれが本明細書に参照として組み込まれる。
治療用組成物の処方およびそれらの続く投与(投薬)は、当業者の技能の範囲内であると考えられる。投薬は、数日間から数カ月間継続する、または治療が効果的になるかもしくは病態の減退が達成されるまでの治療過程において、治療される病態の重症度および応答性に応じて決まる。最適な投薬レジメンは、患者の身体での薬剤蓄積の測定値から算出され得る。当業者であれば、最適投与量、投薬方法および反復頻度を容易に決定できる。最適な投与量は、個々のオリゴヌクレオチドの相対的効力に応じて変動し得、一般に体外および生体内動物モデルにおいて効果的であると判明したEC50に基づいて推定され得る。一般に投与量は、体重1kgあたり0.01μg〜100gであり、1日に、1週間に、1カ月にもしくは1年に1回もしくは複数回またはさらに2〜20年ごとに1回である場合がある。当業者であれば、測定された滞留時間および体液または組織における薬剤の濃度に基づいて投薬の反復頻度を容易に推定できる。治療の成功に続いて、病態の再発を予防するために患者に維持療法を受けさせることが望ましい場合があり、ここでオリゴヌクレオチドは維持投与において体重1kgあたり0.01μg〜100g、1日1回または複数回から20年ごとに1回の範囲で投与される。
上記の通り用語「に特異的なオリゴヌクレオチド」または「オリゴヌクレオチド標的」は、(i)標的遺伝子の一部分と安定な複合体を形成できる配列、または(ii)標的遺伝子のmRNA転写物の一部分と安定な2重鎖を形成できる配列を有するオリゴヌクレオチドを指す。
[HEPG2細胞のアンチセンスオリゴヌクレオチドによる処置]
ATCC(cat#HB−8065)由来のHepG2細胞を増殖培地(MEM/EBSS(Hyclone cat#SH30024またはMediatech cat#MT−10−010−CV)+10%FBS(Mediatech cat#MT35−011−CV)+ペニシリン/ストレプトマイシン(Mediatech cat#MT30−002−CI))中、37℃、5%CO2で増殖させた。実験当日に6穴プレートの培地を新鮮な増殖培地に交換した。全てのアンチセンスオリゴヌクレオチドを濃度20μMに希釈した。この溶液2μlをOpti−MEM培地(Gibco cat#31985−070)400μlおよびLipofectamine 2000(Invitrogen cat#11668019)4μlと室温で20分間インキュベートし、MEPG細胞を含む6穴プレートの各ウエルに添加した。該オリゴヌクレオチド溶液の代わりに水2μlを含む同様の混合物を偽トランスフェクト対照に使用した。37℃、5% CO2での3〜18時間のインキュベーション後、培地を新鮮増殖培地に交換した。アンチセンスオリゴヌクレオチドの添加の48時間後、培地を除去し、Promega製のSV Total RNA Isolation System(cat #Z3105)またはQiagen製のRNeasy Total RNA Isolation kit(cat #74181)を製造者の説明書に従って使用して、RNAを細胞から抽出した。600ngのRNAを、Thermo Scientific製のVerso cDNAキット(cat#AB1453B)またはHigh Capacity cDNA Reverse Transcriptionキット(cat#4368813)を製造者の説明書に記載のとおり使用して得た逆転写反応物に加えた。この逆転写反応からのcDNAを使用して、ABI Taqman gene Expression Mix(cat#4369510)およびABI(Applied Biosystems Taqman Gene Expression Assay:Hs00168927_m1:Applied Biosystems Inc.,Foster City CA)によって設計されたプライマー/プローブを使用するリアルタイムPCRによって遺伝子発現をモニタリングした。使用したPCRサイクルは次の通り:50℃で2分間、95℃で10分間、(95℃で15秒間、60℃で1分間)を40サイクル、Mx4000 thermal cycler(Stratagene)を使用。アンチセンスオリゴヌクレオチドで処置した後の遺伝子発現の変化率を、処置サンプルと偽トランスフェクトサンプルの間の18S標準化dCt値の差に基づいて計算した。
リアルタイムPCR結果によれば、SHBGアンチセンスFXR2(オリゴCUR−1267−1274)と表記された3種のオリゴおよびSHBGアンチセンスSAT2(CUR1275−1280)と表記された4種のオリゴでの処置の48時間後に、HepG2細胞中のSHBGのmRNAレベルは有意に上昇している(図1)。
Claims (18)
- 生体内または体外で患者の細胞または組織における性ホルモン結合グロブリン(SHBG)ポリヌクレオチドの機能および/または発現をアップレギュレートするための、性ホルモン結合グロブリン(SHBG)ポリヌクレオチドの配列番号2または3から選択される天然アンチセンスポリヌクレオチドを標的とし、その配列が配列番号6、8、9、13、15、16、及び17に記載するオリゴヌクレオチド配列から選択される、10〜30個のヌクレオチドの長さの一本鎖アンチセンスオリゴヌクレオチド。
- 性ホルモン結合グロブリン(SHBG)の機能および/または発現が、対照と比較して生体内または体外で増加する、請求項1に記載のアンチセンスオリゴヌクレオチド。
- 前記アンチセンスオリゴヌクレオチドが、少なくとも1つの修飾糖部分、少なくとも1つの修飾ヌクレオチド間結合、少なくとも1つの修飾ヌクレオチド、およびそれらの組み合わせから選択された1以上の修飾を含む、請求項1に記載のアンチセンスオリゴヌクレオチド。
- 前記1以上の修飾が、2’−O−メトキシエチル修飾糖部分、2’−メトキシ修飾糖部分、2’−O−アルキル修飾糖部分、二環糖部分、およびそれらの組み合わせから選択された、少なくとも1つの修飾糖部分を含む、請求項3に記載のアンチセンスオリゴヌクレオチド。
- 前記1以上の修飾は、ホスホロチオアート、アルキルホスホナート、ホスホロジチオエート、アルキルホスホノチオアート、ホスホルアミダート、カルバメート、炭酸塩、リン酸トリエステル、アセトアミダート、カルボキシメチルエステル、およびそれらの組み合わせから選択された少なくとも1つの修飾ヌクレオチド間結合を含む、請求項3に記載のアンチセンスオリゴヌクレオチド。
- 前記1以上の修飾が、ペプチド核酸(PNA)、ロックト核酸(LNA)、アラビノ核酸(FANA)、およびそれらの組み合わせから選択された少なくとも1つの修飾ヌクレオチドを含む、請求項3に記載のアンチセンスオリゴヌクレオチド。
- 少なくとも1つの修飾を含む合成された10〜30個のヌクレオチドの長さの一本鎖オリゴヌクレオチドであって、前記オリゴヌクレオチドの配列は、配列番号6、8、9、13、15、16、及び17に記載するオリゴヌクレオチド配列から選択され、
前記少なくとも1つの修飾が、少なくとも1つの修飾糖部分、少なくとも1つの修飾ヌクレオチド間結合、少なくとも1つの修飾ヌクレオチド、およびそれらの組み合わせから選択されたものであり、
前記オリゴヌクレオチドは、生体内または体外で性ホルモン結合グロブリン(SHBG)遺伝子の配列番号2または3の天然アンチセンスポリヌクレオチドにハイブリダイズし、通常の対照と比較して性ホルモン結合グロブリン(SHBG)遺伝子の機能および/または発現をアップレギュレートするアンチセンス化合物である、オリゴヌクレオチド。 - 前記少なくとも1つの修飾は、ホスホロチオアート、アルキルホスホナート、ホスホロジチオアート、アルキルホスホノチオアート、ホスホルアミダート、カルバメート、炭酸塩、リン酸トリエステル、アセトアミダート、カルボキシメチルエステル、およびそれらの組み合わせからなる群から選択されたヌクレオチド間結合を含む、請求項7に記載のオリゴヌクレオチド。
- 前記オリゴヌクレオチドが、少なくとも1つのホスホロチオアートヌクレオチド間結合を含む、請求項7に記載のオリゴヌクレオチド。
- 前記オリゴヌクレオチドが、ホスホロチオアートヌクレオチド間結合の骨格を含む、請求項7に記載のオリゴヌクレオチド。
- 前記オリゴヌクレオチドは、少なくとも1つの修飾されたヌクレオチドを含み、該修飾されたヌクレオチドは、ペプチド核酸、ロックト核酸(LNA)、およびそれらの組み合わせから選択されたものである、請求項7に記載のオリゴヌクレオチド。
- 前記オリゴヌクレオチドは、複数の修飾を含み、前記複数の修飾は、ホスホロチオアート、アルキルホスホナート、ホスホロジチオアート、アルキルホスホノチオアート、ホスホラミダート、カルバメート、炭酸塩、リン酸トリエステル、アセトアミダート、カルボキシメチルエステル、およびそれらの組み合わせから選択された修飾ヌクレオチドを含む、請求項7に記載のオリゴヌクレオチド。
- 前記オリゴヌクレオチドは複数の修飾を含み、前記複数の修飾は、ペプチド核酸、ロックト核酸(LNA)、およびそれらの組み合わせから選択された修飾ヌクレオチドを含む、請求項7に記載のオリゴヌクレオチド。
- 前記オリゴヌクレオチドが、2’−O−メトキシエチル修飾糖部分、2’−メトキシ修飾糖部分、2’−O−アルキル修飾糖部分、二環糖部分、およびそれらの組み合わせから選択された、少なくとも1つの修飾糖部分を含む、請求項7に記載のオリゴヌクレオチド。
- 前記オリゴヌクレオチドは複数の修飾を含み、前記複数の修飾は、2’−O−メトキシエチル修飾糖部分、2’−メトキシ修飾糖部分、2’−O−アルキル修飾糖部分、二環糖部分、およびそれらの組み合わせから選択された修飾糖部分を含む、請求項7に記載のオリゴヌクレオチド。
- 1以上の請求項7に記載のオリゴヌクレオチドを含む、組成物。
- 前記オリゴヌクレオチドは、1以上の修飾または置換を含む、請求項16に記載の組成物。
- 前記1以上の修飾は、ホスホロチオアート、メチルホスホナート、ペプチド核酸、ロックト核酸(LNA)分子、およびそれらの組み合わせから選択されたものである、請求項17に記載の組成物。
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WO2013080784A1 (ja) | 2011-11-30 | 2013-06-06 | シャープ株式会社 | メモリ回路とその駆動方法、及び、これを用いた不揮発性記憶装置、並びに、液晶表示装置 |
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WO2011085347A2 (en) | 2011-07-14 |
DK2524039T3 (en) | 2018-03-12 |
RU2012127703A (ru) | 2014-02-20 |
CN102803493B (zh) | 2018-07-31 |
EP2524039B1 (en) | 2017-11-29 |
CA2786535C (en) | 2019-03-26 |
CN102803493A (zh) | 2012-11-28 |
RU2611191C2 (ru) | 2017-02-21 |
WO2011085347A3 (en) | 2011-12-29 |
KR20120112530A (ko) | 2012-10-11 |
ES2664866T3 (es) | 2018-04-23 |
EP2524039A2 (en) | 2012-11-21 |
JP2013516197A (ja) | 2013-05-13 |
US20120277290A1 (en) | 2012-11-01 |
US20160046942A1 (en) | 2016-02-18 |
EP2524039A4 (en) | 2013-11-06 |
KR101854926B1 (ko) | 2018-05-04 |
NO2524039T3 (ja) | 2018-04-28 |
US9200277B2 (en) | 2015-12-01 |
CA2786535A1 (en) | 2011-07-14 |
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